Pericardial Toxicities Associated With Immune Checkpoint Inhibitors: A Pharmacovigilance Analysis of the FDA Adverse Event Reporting System (FAERS) Database.

Zhuo Ma,Jiayou Lyu,Lihong Liu,Qixiang Guo,Yuhui Zhang,Jie Pei,Yuwei Liu,Zhixia Zhao,Wenchao Lu,Ximu Sun

doi:10.3389/fphar.2021.663088

Abstract

Introdution: Immune checkpoint inhibitors (ICIs) have significantly improved clinical outcomes for a wide range of cancers but can also lead to serious or fatal immune-related adverse events (irAEs). Although ICI-related pericardial toxicities have been reported, the clinical features are not well characterized in real-world studies. Objective: To characterize the main features of ICI-related pericardial toxicities and identify factors associated with death. Methods: Data from January 1, 2011 to March 31, 2020 in the FDA Adverse Event Reporting System database were retrieved for disproportionality analysis. We used the reporting odds ratio and the information component (IC) to evaluate the association between ICIs and pericardial adverse events. Clinical characteristics of patients with ICI-associated pericardial toxicities were collected and compared between fatal and non-fatal groups. The time to onset following different ICI regimens was further investigated. Results: We identified a total of 705 ICI-associated pericardial toxicities which appeared to influence more men (53.90%) than women (36.03%), with a median age of 63 (interquartile range [IQR] 54–69) years. Patients with lung cancer accounted for the largest proportion (55.6%). ICI therapies were detected with pharmacovigilance signals of pericardial toxicities, corresponding to IC025 = 2.11 and ROR 4.87 [4.51–5.25]. Nevertheless, there was a lack of association between anti-CTLA-4 and pericardial toxicities. There was no difference in onset time among all ICI regimens. However, TTO of fatal cases (25 days (interquartile range [IQR] 6–70)) occurred statistically earlier than non-fatal cases (42 days (IQR 12–114), p = 0.003). Conclusion: ICI monotherapy (PD-1/PD-L1 therapy) and combination therapy can lead to pericardial toxicities that can result in serious outcomes and tend to occur early. Early recognition and management of ICI-related pericardial disorders should attract clinical attention. The findings require further clinical surveillance for the quantification.

Highlights

Immune checkpoint inhibitors (ICIs) are a novel class of medications for cancer and are revolutionizing the treatment of several major cancers (Postow et al, 2015)
ICI monotherapy (PD-1/programmed deathligand 1 (PD-L1) therapy) and combination therapy can lead to pericardial toxicities that can result in serious outcomes and tend to occur early
The FDA Adverse Event Reporting System (FAERS) database recorded 87,404 adverse events related to ICIs and 16,862 reports related to pericardial disorders between January 1 2011 and March 31 2020

Summary

Introduction

Immune checkpoint inhibitors (ICIs) are a novel class of medications for cancer and are revolutionizing the treatment of several major cancers (Postow et al, 2015). The marketed ICIs until recently include programmed death-1 (PD-1) inhibitors (nivolumab, pembrolizumab, cemiplimab), programmed deathligand 1 (PD-L1) inhibitors (atezolizumab, avelumab, durvalumab), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors (ipilimumab, tremelimumab) (Ribas and Wolchok, 2018). Immune-related adverse events (irAEs) associated with the inhibition of immunologic regulation remains a challenge (Postow et al, 2018). Perhaps because of inadequate understanding as a form of ICI-related cardiovascular disorders, data on pericardial disease are derived primarily from case reports and clinical trials that may not correctly represent the real world (Borghaei et al, 2015; Kushnir and Wolf, 2017; Atallah et al, 2019; Yamasaki et al, 2019). The characteristics, timing, outcomes of ICI-related pericardial toxicities and the factors associated with death are still unknown

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